Action Points

Note that this phase II study found that the novel JAK inhibitor peficitinib had efficacy in treating symptomatic rheumatoid arthritis.

Be aware that future studies comparing this therapy to an active control will likely be necessary before broad adoption.

Monotherapy with the oral JAK inhibitor peficitinib appeared effective and safe for moderate-to-severe rheumatoid arthritis in a 12-week phase IIb study, Japanese researchers found.

A 20% response according to the criteria of the American College of Rheumatology (ACR20) was seen in 23.6%, 31.6%, 54.5%, and 65.5% of patients receiving 25 mg, 50 mg, 100, mg, or 150 mg of perficitinib once daily compared with 10.7% of those randomized to placebo, reported Tsutomu Takeuchi, MD, of Keio University in Tokyo, and colleagues.

And serious adverse events were reported in 1.8% of the placebo and 25-mg groups, and in 3.5%, 5.5%, and 0% of patients in the 50-mg, 100-mg, and 150-mg groups, the researchers reported online in Annals of the Rheumatic Diseases.

"Molecules of the signal transduction pathway such as the Janus kinase (JAK) family are considered promising targets for rheumatoid arthritis treatment. JAK1, JAK2, JAK3, and tyrosine kinase 2 form the JAK family of non-receptor protein tyrosine kinases, and are critically important for immune cells and hematopoietic cells," the researchers explained.

Peficitinib inhibits all four members of the JAK family, and is moderately selective for JAK3. Its half-life has been estimated at 7 to 13 hours, suggesting that once-daily dosing might be possible, according to the authors.

To assess the drug's efficacy and safety, the investigators enrolled 281 patients who had six or more tender and six or more swollen joints plus elevated C-reactive protein and/or erythrocyte sedimentation rate.

More than three-quarters of the patients were women. Mean age was 53, and disease duration averaged 7 years.

Up to 30% had previously been treated with an anti-tumor necrosis factor agent, and almost 90% had received methotrexate.

They were randomly assigned to receive placebo or 25 mg, 50 mg, 100 mg, or 150 mg peficitinib once daily for 3 months. A total of 82.6% of patients completed the trial.

Differences from placebo on the primary outcome of ACR20 response at week 12 in the 25-mg, 50-mg, 100-mg, and 150-mg groups were 12.9%, 20.9% (P=0.021), 43.8% (P<0.001), and 54.8% (P<0.001).

The treatment was also effective on the more stringent ACR50 and ACR70 responses, with ACR50 rates of 8.8%, 30.9%, and 29.3% in the 50-mg, 100-mg, and 150-mg groups. ACR70 responses were seen in 1.8%, 16.4%, and 12.1%, respectively.

Low disease activity, defined as a Disease Activity Score in 28 joints (DAS28) below 3.2, was achieved by 38.2% of patients in the 100-mg group and by 39.7% of those in the 150-mg group (P<0.01 for both), while remission, defined as a DAS28 below 2.6, was seen in 27.3% and 20.7%% of those two groups (P<0.01 and P<0.05, respectively).

Significant changes from baseline were apparent by week 2 with the 50-mg to 150-mg doses.

There were no serious infections or malignancies, but herpes zoster developed in two patients in the 25-mg group and two in the 100-mg group.

"It is very important to carefully evaluate the safety of peficitinib in future studies, especially adverse effects related to the suppression of immune functions such as infections, because it has been demonstrated that the JAK inhibitor tofacitinib reduced the T cell stimulatory capacity of human monocyte-derived dendritic cells, and inhibited human B cell activation in an in vitro study," Takeuchi and colleagues wrote.

Worsening of arthritis led to discontinuation in 21 patients, the majority of whom were in the lower dose groups.

One patient with diabetes and hypertension receiving 50 mg died of a cerebral hemorrhage.

More patients in the active treatment groups experienced declines in absolute neutrophil counts and elevations in creatine phosphokinase. There also were increases in LDL and HDL cholesterol, and triglycerides, but no changes in the LDL/HDL ratio.

"The findings of this phase IIb study support the two ongoing phase III studies of peficitinib as an RA treatment option," the investigators concluded.

"This may be a reasonable drug but we will have to see positive results in phase III," noted Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, who was not involved in the study.

"There is not enough information to make a comparison to tofa or bari at present," Fleischmann told MedPage Today, referring to the other JAK inhibitors tofacitinib (Xeljanz) and baricitinib.

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